Spastic paraplegia type 5A

Spastic paraplegia type 5A is a genetic disorder characterized by progressive muscle stiffness and severe weakness primarily affecting the lower limbs, typically manifesting in adolescence and leading to eventual mobility assistance.

Overview

Spastic paraplegia type 5A belongs to a group of genetic disorders known as hereditary spastic paraplegias. These disorders are characterized by muscle stiffness (spasticity) and severe weakness in the lower limbs (paraplegia). Hereditary spastic paraplegias are often divided into two types: pure and complex. The pure types involve spasticity and weakness only in the lower limbs, while the complex types involve additional problems with other areas of the body. Additional features can include changes in vision, changes in intellectual functioning, brain abnormalities, and disturbances in nerve function (neuropathy). Spastic paraplegia type 5A is usually classified as a pure hereditary spastic paraplegia, although complex-type features have been reported in some individuals.

The signs and symptoms of spastic paraplegia type 5A usually appear in adolescence, but they can begin at any time between infancy and mid-adulthood. In addition to spasticity and weakness, people with spastic paraplegia type 5A can lose the ability to sense the position of their limbs or detect vibrations with their lower limbs. They may also have muscle wasting (amyotrophy), reduced bladder control, or high arches of the feet. Some affected individuals have low bone density (osteopenia) or vitamin D deficiency. Affected individuals eventually require walking support, usually around 20 years after symptoms begin, or wheelchair assistance, around 30 years after symptoms begin.

Frequency

There are more than 80 different types of hereditary spastic paraplegia, and the combined prevalence of all these types is estimated to be 1 to 18 in 100,000 people worldwide. Spastic paraplegia type 5A likely accounts for only a small percentage of all hereditary spastic paraplegia cases. More than 50 cases of spastic paraplegia type 5A have been described in the scientific literature.

Causes

Genetic changes that cause disease are called pathogenic variants. Spastic paraplegia type 5A is caused by pathogenic variants in the CYP7B1 gene. This gene provides instructions for making an enzyme called oxysterol 7-alpha-hydroxylase. In the brain, oxysterol 7-alpha-hydroxylase is involved in a pathway that converts certain forms of cholesterol into hormones called neurosteroids. Neurosteroids increase the ability of nerve cells to send signals (excitability). Oxysterol 7-alpha-hydroxylase helps maintain normal cholesterol levels and regulates the effects of neurosteroids.

The CYP7B1 gene variants that cause spastic paraplegia type 5A can reduce or eliminate the activity of oxysterol 7-alpha-hydroxylase. This can prevent the production of neurosteroids and cause cholesterols to accumulate in the brain. The abnormal buildup of cholesterols impairs neuron function and leads to. Low neurosteroid levels likely further impair neuron function by affecting their signaling ability. The loss of neurons results in the deterioration of nervous system functions (neurodegeneration) and causes the movement problems, weakness, and other signs and symptoms that are characteristic of spastic paraplegia type 5A.

Learn more about the gene associated with Spastic paraplegia type 5A

• CYP7B1

Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

• Autosomal recessive spastic paraplegia 5A
• Spastic paraplegia 5
• Spastic paraplegia 5A
• SPG5
• SPG5A